scholarly journals Preclinical Pharmacokinetics, Tissue Distribution, and Primary Safety Evaluation of Indo5, a Novel Selective Inhibitor of c-Met and Trks

2021 ◽  
Vol 12 ◽  
Author(s):  
Teng Luo ◽  
Fei-Xiang Zhang ◽  
Ke Zhao ◽  
Hui-Ying Gao ◽  
Shou-Guo Zhang ◽  
...  
Keyword(s):  
Tissue Distribution ◽  
Intravenous Injection ◽  
Safety Evaluation ◽  
Rat Plasma ◽  
Selective Inhibitor ◽  
Preclinical Pharmacokinetics ◽  
Normal Number ◽  
Liquid Chromatography Tandem Mass ◽  
Tissue Homogenates

The compound [3-(1H-benzimidazol-2-methylene)-5-(2-methylphenylaminosulfo)-2-indolone], known as Indo5, is a novel selective inhibitor of c-Met and Trks, and it is a promising anticancer candidate against hepatocellular carcinoma (HCC). Assessing the pharmacokinetic properties, tissue distribution, and toxicity of Indo5 is critical for its medicinal evaluation. A series of sensitive and specific liquid chromatography-tandem mass spectrometry methods were developed and validated to determine the concentration of Indo5 in rat plasma and tissue homogenates. These methods were then applied to investigate the pharmacokinetics and tissue distribution of Indo5 in rats. After intravenous injection of Indo5, the maximum concentration (Cmax) and the time at which Cmax was reached (Tmax) were 1,565.3 ± 286.2 ng/ml and 1 min, respectively. After oral administration, Cmax and Tmax were 54.7 ± 10.4 ng/ml and 2.0 ± 0.48 h, respectively. We calculated the absolute oral bioavailability of Indo5 in rats to be 1.59%. Following intravenous injection, the concentrations of Indo5 in various tissues showed the following order: liver > kidney ≈ heart > lung ≈ large intestine ≈ small intestine ≈ stomach > spleen > brain ≈ testes; hence, Indo5 distributed highest in the liver and could not cross the blood–brain or blood–testes barriers. Continuous injection of Indo5 for 21 days did not lead to liver injury, considering unchanged ALT and AST levels, normal histological architecture of the liver, and normal number and frequencies of immune cells in the liver, indicating a very low toxicity of Indo5 in vivo. Collectively, our findings provide a comprehensive understanding of the biological actions of Indo5 in vivo and further support its development as an antitumor treatment for HCC patients.

scholarly journals HPLC-MS/MS-Mediated Analysis of the Pharmacokinetics, Bioavailability, and Tissue Distribution of Schisandrol B in Rats

2021 ◽  
Vol 2021 ◽  
pp. 1-12 ◽  
Author(s):  
Dahu Liang ◽  
Zijing Wu ◽  
Yanhao Liu ◽  
Chao Li ◽  
Xianghong Li ◽  
...  
Keyword(s):  
Tissue Distribution ◽  
Oral Bioavailability ◽  
Internal Standard ◽  
Rat Plasma ◽  
Absolute Bioavailability ◽  
Sprague Dawley ◽  
Linear Calibration ◽  
Tissue Homogenates ◽  
Distribution Studies

Schisandrol B, a lignan isolated from dried Schisandra chinensis fruits, has been shown to exhibit hepatoprotective, cardioprotective, renoprotective, and memory-enhancing properties. This study sought to design a sensitive and efficient HPLC-MS/MS approach to measuring Schisandrol B levels in rat plasma and tissues in order to assess the pharmacokinetics, oral bioavailability, and tissue distributions of this compound in vivo. For this analysis, bifendate was chosen as an internal standard (IS). A liquid-liquid extraction (LLE) approach was employed for the preparation of samples that were subsequently separated with an Agilent ZORBAX Eclipse XDB-C18 (4.6 × 150 mm, 5 μm) column with an isocratic mobile phase consisting of methanol and water containing 5 mM ammonium acetate and 0.1% formic acid (90 : 10, v/v). A linear calibration curve was obtained over the 5–2000 ng/mL and 1–1000 ng/mL ranges for plasma samples and tissue homogenates, respectively. This established method was then successfully applied to investigate the pharmacokinetics, oral bioavailability, and tissue distributions of Schisandrol B in Sprague-Dawley (SD) rats that were intravenously administered 2 mg/kg of Schisandrol B monomer, intragastrically administered Schisandrol B monomer (10 mg/kg), or intragastrically administered 6 mL/kg SCE (equivalent to 15 mg/kg Schisandrol B monomer). The oral absolute bioavailability of Schisandrol B following intragastric Schisandrol B monomer and SCE administration was approximately 18.73% and 68.12%, respectively. Tissue distribution studies revealed that Schisandrol B was distributed throughout several tested tissues, with particular accumulation in the liver and kidneys. Our data represent a valuable foundation for future studies of the pharmacologic and biological characteristics of Schisandrol B.

scholarly journals A Validated HPLC-MS/MS Assay for 14-O-[(4,6-Diaminopyrimidine-2-yl)thioacetyl] Mutilin in Biological Samples and Its Pharmacokinetic, Distribution and Excretion via Urine and Feces in Rats

Molecules ◽  
2019 ◽  
Vol 24 (4) ◽  
pp. 790 ◽  
Author(s):  
Yunxing Fu ◽  
Yu Liu ◽  
Yunpeng Yi ◽  
Jianping Liang ◽  
Qingfeng Wu ◽  
...  
Keyword(s):  
Tissue Distribution ◽  
Matrix Effects ◽  
Limit Of Detection ◽  
Internal Standard ◽  
Pharmacokinetic Profile ◽  
Rat Plasma ◽  
Gram Positive Bacteria ◽  
The Matrix ◽  
Tissue Homogenates

14-O-[(4,6-Diaminopyrimidine-2-yl)thioacetyl] mutilin (DPTM), a novel pleuromutilin candidate with a substituted pyrimidine moiety, has been confirmed to possess excellent antibacterial activity against Gram-positive bacteria. To illustrate the pharmacokinetic profile after intravenous (i.v.), intramuscular (i.m.) and oral (p.o.) administrations with DPTM, as well as tissue distribution and excretion via urine and feces in vivo, a specific, sensitive and robust HPLC-MS/MS method was first developed to determine DPTM in rat plasma, various tissues, urine and feces. The plasma, tissues, urine and feces samples were treated by protein precipitation with acetonitrile using tiamulin fumarate as an internal standard (IS). This method which was achieved on an HPLC system detector equipped with an ESI interface, was sensitive with 5 ng/mL as the lower limit of detection and exhibited good linearity (R2 > 0.9900) in the range of 5–4000 ng/mL for plasma, various tissues, urine and feces, as well as intra-day precision, inter-day precision and accuracy. The matrix effects ranged from 94.2 to 109.7% with RSD ≤ 9.4% and the mean extraction recoveries ranged from 95.4 to 109.5% in plasma, tissue homogenates, urine and feces (RSD ≤ 9.9). After i.v., i.m. and p.o. administrations, DPTM was rapidly absorbed and metabolized in rats with the half-life (t1/2) of 1.70–1.86, 3.23–3.49 and 4.38–4.70 for 10, 25 and 75 mg/kg doses, respectively. The tissue distribution showed that DPTM was diffused into all the tested tissues, especially into the intestine and lung. Excretion via urine and feces studies demonstrated that DPTM was mainly excreted by feces after administration.

Ex vivo measurement of tissue distribution of a nitroxide radical after intravenous injection and its in vivo imaging using a rapid scan ESR-CT system

2000 ◽  
Vol 18 (2) ◽  
pp. 151-156 ◽  
Author(s):  
Hitoshi Togashi ◽  
Taku Matsuo ◽  
Haruhide Shinzawa ◽  
Yoshio Takeda ◽  
Li Shao ◽  
...  
Keyword(s):  
Tissue Distribution ◽  
Intravenous Injection ◽  
In Vivo Imaging ◽  
Ex Vivo ◽  
Nitroxide Radical ◽  
Rapid Scan ◽  
Ct System

scholarly journals Preclinical Pharmacokinetics of Scoparone, Geniposide and Rhein in an Herbal Medicine Using a Validated LC-MS/MS Method

Molecules ◽  
2018 ◽  
Vol 23 (10) ◽  
pp. 2716 ◽  
Author(s):  
Tun-Pin Hsueh ◽  
Tung-Hu Tsai
Keyword(s):  
Bioactive Compounds ◽  
Pharmacokinetic Study ◽  
High Performance ◽  
Low Dose ◽  
Rat Plasma ◽  
Herbal Formula ◽  
Preclinical Pharmacokinetics ◽  
Pharmacokinetic Properties ◽  
Liquid Chromatography Tandem Mass

The herbal formula Yin-Chen-Hao-Tang has been reported to have anti-fibrosis properties. The aim of this study was to reveal the pharmacokinetic characteristics of bioactive compounds in this herbal formula. A new high-performance liquid chromatography-tandem mass spectrometry method was developed and validated for simultaneous determination of scoparone, geniposide and rhein in rat plasma. A pharmaceutical herbal powder was administered to rats at doses of 1 g/kg and 3 g/kg orally. The method showed excellent linearity (r2 > 0.999) and validation was successfully conducted for the pharmacokinetic study. The results show that the Cmax values and areas under the curve of scoparone, geniposide and rhein were higher and not proportional to the dose in rat plasma, while the Tmax and half-life values were consistent in the group that received 1 g/kg. The clearance of the higher dose (3 g/kg) did not decrease proportionally to that of the low dose. The results showed the nonlinear pharmacokinetic properties of scoparone, geniposide and rhein in Yin-Chen-Hao-Tang that suggested possible accumulation of bioactive compounds through oral administration. This pharmacokinetic study reveals that an increased dose of this herbal formula would largely increase the maximum concentration and bioavailability of scoparone, geniposide and rhein.

scholarly journals An LC-MS/MS Method for Simultaneous Determination of the Toxic and Active Components of Cortex Periplocae in Rat Plasma and Application to a Pharmacokinetic Study

2019 ◽  
Vol 2019 ◽  
pp. 1-10 ◽  
Author(s):  
Zhen Li ◽  
Yang Li ◽  
Jin Li ◽  
Rui Liu ◽  
Jia Hao ◽  
...  
Keyword(s):  
Oral Administration ◽  
Multiple Reaction Monitoring ◽  
Gradient Elution ◽  
Rat Plasma ◽  
Pharmacokinetic Studies ◽  
Simple Liquid ◽  
Active Components ◽  
Limit Of Quantification ◽  
Liquid Chromatography Tandem Mass

A sensitive and simple liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated to simultaneously determine the toxic and other active components including isovanillin, scopoletin, periplocin, periplogenin, and periplocymarin after oral administration of cortex periplocae extract to rats. Plasma samples were prepared by protein precipitation with methanol. All compounds were separated on a C18 column with gradient elution using acetonitrile and formic acid aqueous solution (0.1%, v/v) as the mobile phase at a flow rate of 0.3 mL/min. The detection of all compounds was accomplished by multiple-reaction monitoring (MRM) in the positive electrospray ionization mode. The LC-MS/MS method exhibited good linearity for five analytes. The lower limit of quantification (LLOQ) was 0.48 ng/mL for scopoletin, periplogenin, and periplocymarin; 2.4 ng/mL for isovanillin and periplocin. The extraction recoveries of all compounds were more than 90% and the RSDs were below 10%. It was found that the absorption of scopoletin and periplocin was rapid in vivo after oral administration of cortex periplocae extract. Furthermore, periplocymarin possessed abundant plasma exposure. The results demonstrated that the validated method was efficiently applied for the pharmacokinetic studies of isovanillin, scopoletin, periplocin, periplogenin, and periplocymarin after oral administration of cortex periplocae extract.

scholarly journals Simultaneous Measurement of Tadehaginoside and its Principal Metabolite in Rats by HPLC–MS/MS and its Application in Pharmacokinetics and Tissue Distribution Study

2021 ◽  
Author(s):  
Cai-Yun Zhang ◽  
Ya-Ting Lu ◽  
Yin-Feng Tan ◽  
Lin Dong ◽  
Zhi-Heng Su ◽  
...  
Keyword(s):  
Tissue Distribution ◽  
High Performance ◽  
Biological Activities ◽  
Intragastric Administration ◽  
Distribution Study ◽  
Chromatography Tandem Mass Spectrometry ◽  
Liquid Chromatography Tandem Mass ◽  
Tissue Distribution Study

Abstract Background Tadehaginoside, an active ingredient isolated from Tadehagi triquetrum L., exhibited various biological activities. However, the pharmacokinetics and tissue-distribution which affects tadehaginoside’s therapeutic actions and application remain elusive.MethodsTo clarify the metabolism of tadehaginoside in vivo, a high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method was established to detect the level of tadehaginoside in plasma and eleven tat tissues (brain, heart, liver, spleen, lungs, kidneys, stomach, small intestine, skeletal muscle, body fat, and testes). Besides, this validated method was also successfully applied to the quantitative determination of its metabolite, p-hydroxycinnamic acid (HYD) in plasma. The pharmacokinetic and tissue-distribution of tadehaginoside were investigated by this developed method. ResultsThe pharmacokinetic study indicated that tadehaginoside in plasma of rats with intragastric administration showed relatively low concentration may be due to the formation of its metabolite, and the quick absorption of tadehaginoside was detected following intravenous administration. Tissue-distribution study indicated that kidney and spleen were the major distribution organs for tadehaginoside in rats. ConclusionsThese results could provide clues for exploring the bioactivity of tadehaginoside based on its pharmacokinetic characteristics.

scholarly journals Development and Validation of a UPLC-MS/MS Method for the Quantitative Determination and Pharmacokinetic Analysis of Cirsimarin in Rat Plasma

2021 ◽  
Vol 2021 ◽  
pp. 1-7
Author(s):  
En Zhang ◽  
Ying Wang ◽  
Fuyi Xie ◽  
Xinlei Zhuang ◽  
Xianqin Wang ◽  
...  
Keyword(s):  
Intravenous Administration ◽  
High Performance ◽  
Rat Plasma ◽  
Biological Properties ◽  
Pharmacokinetic Analysis ◽  
Standard Curve ◽  
The Matrix ◽  
Liquid Chromatography Tandem Mass ◽  
Development And Validation

Cirsimarin is a bioactive antilipogenic flavonoid isolated from the cotyledons of Abrus precatorius and represents one of the most abundant flavonoids present in this plant species. Cirsimarin exhibits excellent antioxidant, lipolysis, and other biological properties; it can effectively trigger lipid movement and demonstrates antiobesity effects. In this work, an ultra-high-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method was developed for the determination of cirsimarin in rat plasma after intravenous administration. A standard curve of cirsimarin in blank rat plasma was generated over the concentration range of 1–3000 ng/mL. Six rats were administered cirsimarin intravenously (1 mg/kg). The method only required 50 μL of plasma for sample preparation, and the plasma proteins were precipitated with acetonitrile to pretreat the plasma sample. The precisions of cirsimarin in rat plasma were less than 14%, while the accuracies varied between 92.5% and 107.3%. In addition, the matrix effect varied between 103.6% and 107.4%, while the recoveries were greater than 84.2%. This UPLC-MS/MS method was then applied in measuring the pharmacokinetics of cirsimarin in rats. The AUC(0-t) values of cirsimarin from the pharmacokinetic analysis were 1068.2 ± 359.2  ng/mL·h for intravenous administration. The half-life ( t 1 / 2 ) was 1.1 ± 0.4  h (intravenous), indicating that the metabolism of the compound was quick in the rats. Exploring the pharmacokinetics of cirsimarin in vivo can help better understand its metabolism.

scholarly journals Pharmacokinetics of ligustroflavone in rats and tissue distribution in mice by UPLC–MS/MS

2020 ◽  
Vol 32 (2) ◽  
pp. 102-106 ◽  
Author(s):  
Quan Zhou ◽  
Zhiguang Zhang ◽  
Peiwu Geng ◽  
Bingge Huang ◽  
Xianqin Wang ◽  
...  
Keyword(s):  
Tissue Distribution ◽  
Intraperitoneal Administration ◽  
Ultra Performance Liquid Chromatography ◽  
Rat Plasma ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
Mouse Tissues ◽  
Extensive Metabolism ◽  
Liquid Chromatography Tandem Mass ◽  
Group 1

An ultra-performance liquid chromatography–tandem mass spectrometry (UPLC–MS/MS) method was developed and validated for quantification of ligustroflavone, which was then applied in pharmacokinetics study in rat and tissue distribution in mouse. Twelve male Sprague Dawley rats were used for pharmacokinetics after intravenous (2 or 8 mg/kg) administration of ligustroflavone, six rats for each dose. Twenty-five mice were randomly divided into 5 groups (5 mice for each group, 1 group for each time point) and received 16 mg/kg ligustroflavone via intraperitoneal administration. The linear range of the calibration curve was over 2–2000 ng/mL for ligustroflavone in rat plasma and mouse tissues. The intra-day and inter-day precision expressed in % RSD were less than 14%, and the accuracy was between 88.5% and 108.4%. The tissue distribution results indicated that ligustroflavone diffuses rapidly and widely into major organs. The level of ligustroflavone was highest in the mouse liver, followed by the kidney, spleen, and lung. The overwhelming accumulation in the liver indicated that the liver was responsible for the extensive metabolism.

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